Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies

a technology of amyloid disease and synucleinopathies, which is applied in the field of substituted naryl benzamides and related compounds, pharmaceutical compositions, can solve the problems of toxic and neuronal cell death, no cure or effective treatment, and amyloid deposition can be detrimental to the patient, and achieve enhanced efficacy and metabolic optimization

Inactive Publication Date: 2011-05-05
PROTEOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0027]In one embodiment, substitutents are appropriately selected to optimize physicochemical and / or biological properties such as, bioavailability, pharmacokinetics, blood-brain barrier penetration, optimized metabolism, and enhanced efficacy for treatment of amyloid diseases and synucleinopathies.

Problems solved by technology

Fibrillar Aβ amyloid deposition in Alzheimer's disease is believed to be detrimental to the patient and eventually leads to toxicity and neuronal cell death, characteristic hallmarks of Alzheimer's disease.
In Alzheimer's disease, Parkinson's and “systemic” amyloid diseases, there is currently no cure or effective treatment, and the patient usually dies within 3 to 10 years from disease onset.
For most of these amyloidoses, there is no apparent cure or effective treatment and the consequences of amyloid deposition can be detrimental to the patient.
For example, amyloid deposition in the kidney may lead to renal failure, whereas amyloid deposition in the heart may lead to heart failure.
Alzheimer's disease also puts a heavy economic burden on society.
For a disease that can span from 2 to 20 years, the overall cost of Alzheimer's disease to families and to society is staggering.

Method used

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  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies
  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies
  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies

Examples

Experimental program
Comparison scheme
Effect test

example 1

HPLC Method

[0139]For the following synthetic methods this HPLC method was employed. Samples were analysed using an Agilent HP1100 instrument, operated with EzChrom Elite software, and fitted with a C18 column (Phenomenex Prodigy 5 μm 100A, 250×4.6 mm) with a guard column (Phenomenex ODS 4×3 mm, 5 μm) held at 30° C. Peaks were detected at 280 nm. The mobile phase was acetonitrile in water (with 0.1% TFA): t0=11%, t20=11%, t30=100%, t31=11%, t40=11%. The flow rate was 1 mL / min and the injection volume of 5 μL.

Overview of Synthesis of N-(2-fluoro-4,5-dihydroxyphenyl)-3,4-dihydroxy benzamide (DC51-F5)

[0140]Nitration (I. M. Takakis et al. I Heterocyclic Chem. 1991, 28, 625-634) of commercially available 4-fluoroveratrole gave, as expected, just the 2-nitro isomer 1, as shown by NMR. Reduction using tin II chloride (A. Kamal et al. Bioorg. Med. Chem. 2007, 15 (22), 6868-6875) of this gave the aniline 2, which was immediately reacted with 3,4-methylenedioxybenzoyl chloride to give the anil...

example 2

Overview of Synthesis of Positional isomers N-(3-fluoro-4,5-dihydroxyphenyl)-3,4-dihydroxy benzamide (DC51-F4) and N-(2-fluoro-3,4-dihydroxyphenyl)-3,4-dihydroxy benzamide (DC51-F6)

[0154]3-Fluoroveratrole 4 was prepared by methylation4 of the commercially available 3-fluorocatechol. Nitration of 3-fluoroveratrole gave a mixture of the two isomeric products 5 and 6 in a 2:1 ratio (structures and ratio determined by NMR spectroscopy). Separation of these, followed by reduction with tin II chloride3 gave the anilines 7 and 8. Reaction of the anilines with 3,4-methylenedioxybenzoyl chloride gave the anilides 9 and 10. Deprotection with boron tribromide under standard conditions gave the free phenolic anilides, N-(3-fluoro-4,5-dihydroxyphenyl)-3,4-dihydroxybenzamide (DC51-F4) and N-(2-fluoro-3,4-dihydroxyphenyl)-3,4-dihydroxybenzamide (DC51-F6) in reasonable yield.

Step A: Preparation of 1-fluoro-2,3-dimethoxy-5-nitrobenzene (5) and 1-fluoro-2,3-dimethoxy-6-nitrobenzene (6)

[0155]To ice co...

example 3

Overview of Synthesis of N-(3,4-dihydroxyphenyl)-2-fluoro-4,5-dihydroxy benzamide (DC51-F2)

[0178]Oxidation of commercially available 6-fluoroveratraldehyde with ‘Jones reagent'6 gave the acid 11 in good yield. Formation of’ the acid chloride from this and condensation with 3,4-methylenedioxyaniline then gave the anilide 12. Deprotection with boron tribromide under standard conditions gave the free phenolic anilide, DC51-F2 in good yield.

Step A: Preparation of 2-fluoro-4,5-dimethoxybenzoic acid (11)

[0179]To a stirred solution of 2-fluoro-4,5-dimethoxybenzaldehyde (0.46 g, 2.5 mmol) in acetone (20 ml) was added Jones reagent (6 ml) dropwise and the mixture stirred at RT for 4 h (P. B. Wakchaure et al. Tetrahedron 2008, 64, 1786-1791.). The mixture was diluted with water, extracted into ethyl acetate then dried and evaporated in vacuo to give the crude acid. Recrystallisation from ethyl acetate / pet ether (40-60) gave the pure acid as a brown crystalline solid (H. B. Stegmann et al. J.C...

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Abstract

Compounds and their pharmaceutically acceptable salts, their synthesis and labeling, pharmaceutical compositions containing them, and their use in the treatment of amyloid diseases, including Aβ amyloidosis, such as observed in Alzheimer's disease, IAPP amyloidosis, such as observed in type 2 diabetes, and synucleinopathies, such as observed in Parkinson's disease, and the manufacture of medicaments for such treatment are provided. Also provided is the use of the disclosed compounds as imaging agents and methods for in vivo imaging and detection of amyloid and synuclein.

Description

RELATED APPLICATIONS[0001]This application is a continuation in part of U.S. application Ser. No. 12 / 201,183 filed Aug. 29, 2008 which is a continuation in part of U.S. application Ser. No. 11 / 328,748, now issued U.S. Pat. No. 7,745,490, which is a continuation of U.S. application Ser. No. 11 / 129,771, filed May 12, 2005, entitled “Substituted N-Aryl Benzamides and Related Compounds for Treatment of Amyloid Diseases and Synucleinopathies” now abandoned. U.S. application Ser. No. 11 / 129,771 claimed priority under 35 U.S.C. §119(e) to U.S. provisional application Ser. Nos. 60 / 570,669, entitled “Substituted N-Aryl Benzamides and Related Compounds for Treatment of Amyloid Diseases and Synucleinopathies” to Snow et al., filed May 12, 2004 and 60 / 629,525, entitled “Substituted N-Aryl Benzamides and Related Compounds for Treatment of Amyloid Diseases and Synucleinopathies” to Snow et al., filed Nov. 18, 2004.[0002]This application is also a continuation in part of U.S. application Ser. No. ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/167C07C233/75A61K51/00A61P43/00
CPCC07C235/56A61P43/00
Inventor SNOW, ALANWEIGELE, MANFREDLARSEN, LESLEYNGUYEN, BETHLAKE, THOMASCASTILLO, GERARDOSANDERS, VIRGINIAWEAVERS, REX T.LORIMER, STEPHENLARSEN, DAVIDCOFFEN, DAVID L.COFFEN, CHARLOTTE
Owner PROTEOTECH
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